There is currently no effective therapy for men with metastatic prostate cancer who relapse after androgen ablation, even though numerous agents have been tested over the past thirty years. Prolonged administration of effective concentrations of standard chemotherapeutic agents is usually not possible because of dose-limiting systemic toxicities.
PSMA is a 100 kDa prostate epithelial cell type II transmembrane glycoprotein that was originally isolated from a cDNA library from the androgen responsive LNCaP human prostate cancer cell line, as disclosed, for example by Horoszewicz et al., Cancer Res. 43:1809-1818, (1980). Immunohistochemical studies using monoclonal antibodies have demonstrated that PSMA is expressed by normal prostate epithelium and is even more highly expressed by a large proportion of prostate cancers, including metastatic prostate cancers, as disclosed, for example in Horoszewicz et al.; Wright et al., Urol. Oncol. 1:18-28, (1995); and Lopes et al., Cancer Res. 50:6423-6429, (1990). Low-level detection of the PSMA protein has also been seen in the duodenal mucosa and in a subset of proximal renal tubules. In all other human tissues, including normal vascular endothelium, PSMA expression was not detectable, as disclosed for example, in Silver et al., Clin. Cancer Res. 3:81-85, (1997); and Chang et al., Cancer Res. 59:3192-3198, (1999). PSMA, however, has been detected in the neovasculature of a large number of different tumor types including breast, renal, colon, pancreatic, brain, melanoma, lung, testicular, sarcoma and transitional cell carcinomas (Silver et al., and Chang et al.).
Two discrete enzymatic functions for PSMA have been described. Carter et al., Proc. Natl. Acad. Sci., USA 93:749-753, (1996), demonstrated that PSMA possesses the hydrolytic properties of an N-acetylated α-linked acidic dipeptidase (NAALADase). NAALADase is a membrane hydrolase activity that is able to hydrolyze the neuropeptide N-acetyl-l-aspartyl-l-glutamate (NAAG) to yield the neurotransmitter glutamate and N-acetyl-aspartate. In addition to the NAALADase activity, PSMA also functions as a pteroyl poly-γ-glutamyl carboxypeptidase (folate hydrolase), as disclosed, for example, by Pinto et al., Clin. Cancer Res. 2:1445-1451, (1996). PSMA exhibits exopeptidase activity and has more recently been classified as glutamate carboxypeptidase II. It is able to progressively hydrolyze γ-glutamyl linkages of both poly-γ-glutamated folates and methotrexate analogs with varying length glutamate chains, as disclosed, for example, in Pinto et al., and Heston et al., Urology 49 (Suppl 3A): 104-112, (1997). PSMA is able to progressively hydrolyze γ-glutamyl linkages of both poly-gamma glutamated folates and poly-gamma glutamated methotrexate analogs with varying length glutamate chains. Unfortunately, it has also been found that these polyglutamated analogs can also be readily hydrolyzed by gamma glutamyl hydrolase (GGH), a lysosomal enzyme. Gingras et al. recently characterized a human blood plasma glutamate carboxypeptidase (PGCP) that has significant sequence homology to PSMA and glutamate carboxypeptidase activity, see J. Biol. Chem. 274:11742-11750, (1999). Proteins that are homologous to PSMA have been recently isolated from the rat brain and pig jejunum, as disclosed, for example, in Luthi-Carter et al., Proc. Natl. Acad. Sci. USA 95:3215-3220, (1998); and Halsted et al., J. Biol. Chem. 273:20417-20424, (1998). These proteins have >80% amino acid sequence homology with PSMA and possess similar enzymatic functions.